Bortezomib, Rituximab, and Dexamethasone With or Without Temsirolimus in Treating Patients With Untreated or Relapsed Waldenstrom Macroglobulinemia or Relapsed or Refractory Mantle Cell or Follicular Lymphoma

This randomized phase I/II trial studies the side effects and the best dose of temsirolimus when given together with bortezomib, rituximab, and dexamethasone and to see how well they work compared to bortezomib, rituximab, and dexamethasone alone in treating patients with untreated or relapsed Waldenstrom macroglobulinemia or relapsed or refractory mantle cell or follicular lymphoma. Bortezomib and temsirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Bortezomib may also stop the growth of cancer cells by blocking blood flow to the tumor. Monoclonal antibodies, such as rituximab, can block cancer growth in difference ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not yet known whether bortezomib, rituximab, and dexamethasone are more effective with temsirolimus in treating non-Hodgkin lymphoma.

Dose-limiting toxicity (DLT) is based on the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).

Progression-free survival (PFS) of patients treated with temsirolimus in combination with bortezomib, rituximab, and dexamethasone (Phase II) [ Time Frame: Time from randomization until disease progression or death of any cause, assessed up to 10 years ] [ Designated as safety issue: No ]

PFS distributions will be estimated using the method of Kaplan and Meier. The primary analysis of PFS will be performed using a stratified log-rank test with an approximate overall one-sided alpha = 0.15.

Secondary Outcome Measures:

Change in the Functional Assessment of Cancer Therapy (FACT)-Fatigue Trial Outcome Index (TOI) score between the two treatment arms [ Time Frame: Baseline up to 3 years ] [ Designated as safety issue: No ]

Descriptive statistics on the number of responses along with the mean and standard deviations of FACT-Fatigue TOI scores within each treatment arm at each time point will be provided.

Duration of response (Phase II) [ Time Frame: From first observation of a response (minimal response or better) to the time of disease progression, with deaths due to causes other than progression censored, assessed up to 10 years ] [ Designated as safety issue: No ]

Overall survival of patients (Phase II) [ Time Frame: From date of study entry until date of death, assessed up to 10 years ] [ Designated as safety issue: No ]

Response rates and duration of response (Phase II) [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]

Major/Objective Response (OR) is defined as achieving partial response or better by the end of protocol treatment. Minor Response (MR) is defined as achieving minor response or better by the end of protocol treatment.

Time to disease progression (Phase II) [ Time Frame: From registration to first observed progression or censored at date of last disease assessment without progression, assessed up to 10 years ] [ Designated as safety issue: No ]

Time to next therapy (Phase II) [ Time Frame: From the end of treatment to the initiation of next therapy, censored at date last known alive without initiation of next therapy, assessed up to 10 years ] [ Designated as safety issue: No ]

Patients receive rituximab IV over 30-60 minutes on days 1, 8, 15, and 22 (of courses 1 and 4 only) and bortezomib IV or SC and dexamethasone PO on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22 and rituximab, bortezomib, and dexamethasone as in arm I. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

OUTLINE: This is a phase I, dose-escalation study of temsirolimus followed by a randomized phase II study.

PHASE I: Patients receive temsirolimus intravenously (IV) over 30-60 minutes on days 1, 8, 15, and 22; rituximab IV over 30-60 minutes on days 1, 8, 15, and 22 (of courses 1 and 4 only); and bortezomib IV or subcutaneously (SC) and dexamethasone orally (PO) on days 1, 8, and 15. Courses repeat every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive rituximab IV over 30-60 minutes on days 1, 8, 15, and 22 (of courses 1 and 4 only) and bortezomib IV or SC and dexamethasone PO on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22 and rituximab, bortezomib, and dexamethasone as in arm I. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly for 5 years.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Histologically proven diagnosis

For phase I portion (Arm A, B, C and D), patients must have of one of the following:

Relapsed Waldenstrom's macroglobulinemia

Relapsed/refractory mantle cell lymphoma; previous treatment with at least one standard regimen and no longer responsive to that regimen

Relapsed/refractory follicular lymphoma; previous treatment with at least one standard regimen and no longer responsive to that regimen

Relapsed/refractory marginal zone lymphoma; previous treatment with at least one standard regimen and no longer responsive to that regimen

Relapsed/refractory small lymphocytic lymphoma; previous treatment with at least one standard regimen and no longer responsive to that regimen

For phase II portion (Arm E and F), patients must have a diagnosis of symptomatic Waldenstrom's macroglobulinemia, either untreated or relapsed, confirmed by the presence of all of the following:

Bone marrow lymphoplasmacytosis with

>= 10% lymphoplasmatic cells (measured within 28 days prior to registration) OR

Aggregates or sheets of one of the following: lymphocytes, plasma cells or lymphoplasmacytic cells on the bone marrow biopsy (measured within 28 days prior to registration)

In addition to measurable disease, patients must have symptomatic disease defined by one or more of the following:

Laboratory studies defining eligibility (hemoglobin [Hgb], platelet count, viscosity) must have been obtained within 28 days prior to registration; if more than one test was obtained, the most recent one will be utilized

NOTE: in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication; patients cannot be enrolled if they do not meet these criteria on or off lipid lowering medication; patients must start lipid lowering medication and cholesterol and triglycerides must be below said levels before study entry

Patients must not have had prior exposure to mammalian target of rapamycin (m-TOR) inhibitors (sirolimus, temsirolimus, everolimus)

Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Women of childbearing potential and sexually active males must use an accepted and effective method of contraception throughout the study and for 8 weeks following discontinuation of everolimus

Patients must have no history of prior malignancy except for adequately treated basal cell or squamous cell skin cancer or in-situ cervical cancer; the patient may also have had other cancer for which the patient was curatively treated with surgery alone and from which the patient has been disease free for >= 5 years

Severely impaired lung function as defined as spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for Hgb) that is < 50% of the normal predicted value and/or oxygen (O2) saturation < 88% at rest on room air

Active (acute or chronic) or uncontrolled severe infections

Patients must have Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging Network (ACRIN) performance status of =< 2

Patients must not have grade 2 or higher neuropathy

Patients must not have concurrent use of angiotensin-converting enzyme (ACE) inhibitors (angioedema), and no concurrent use of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers and inhibitors

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01381692